1. Field of the Invention
The present invention relates to the fields of immunology and allergology. More specifically, the present invention discloses monoclonal antibodies to allergen and their use in prevention of allergic symptoms.
2. Description of the Related Art
Hypersensitivity to aeroallergens is a major cause of allergic diseases, e.g. bronchial asthma, allergic rhinitis and allergic conjunctivitis), that affect up to 30% of some populations (1-2). In the United States, about 39 million persons were estimated to have experienced allergic rhinitis (3). Symptoms of rhinitis and asthma due to aeroallergens cause extensive morbidity, lost productivity and increased health care cost (4). Allergic rhinitis accounts for more than 10 million office visits for medical care and millions of days of restricted activity each year in the U.S. The clinical efficacy of the current pharmaco- and immunotherapy for plant-induced allergic diseases is limited. The total monetary cost of the condition is estimated to be $6 billion.
The pollen of various plants, including trees, grasses and weeds are responsible for many of the allergic reactions that occur outdoor during specific seasons. Cedar hypersensitivity is one of the most common causes of seasonal allergic disease in numerous regions around the world. Japanese cedar (Cryptomeria japonica, Taxodiaceae) is the major cause of pollinosis in Japan (5), while mountain cedar (Juniperus ashei, Cupressaceae) pollen caused severe seasonal allergic rhinitis in North America (particularly, Arkansas, Oklahoma, central Texas, and Northern Mexico) (6-7) and Arizona and italian cypresses (Cupressus arizonica and simperverins, Cupressaceae) causes pollinosis in the Mediterranean region (France, Italy and Israel) (8-9).
Additionally, individuals with hypersensitivity to one member of the Cupressaceae and Taxodiaceae families have been shown to have extensive cross-reactivity to other members of the Cupressaceae family by acute hypersensitivity skin testing (7). This could be due to similarities in the structures of the proteins in the pollen from different trees.
Altered regulation of IgE antibody formation is the hallmark of the allergic diathesis. Normal individuals exposed to inhaled aeroallergens produce small amounts of IgG1 and IgG4 antibodies in association with proliferation of T helper 1 (Th1) cells. Patients with an allergic diathesis tend to have exaggerated responses of their T helper 2 (Th2) cells and produce large amount of allergen-specific IgE (10). This “allergic” response is most likely due at least in part, to genetic propensities to overexpress families of cytokine genes, e.g. IL-4, IL-5 and IL-13. However, the process of allergic sensitization also depends on the amount, duration and group of allergen exposures. In general, small concentrations of allergenic protein delivered to the mucosal surface are most effective in this respect (11). Allergic or atopic individuals typically have elevated serum IgE concentrations and IgE antibodies to multiple epitopes of a number of environmental allergens. When the IgE near the mucosal surface reaches a high enough concentration and is directed against an adequate number of epitopes on the allergen, an allergic reaction can ensue.
The immune complexes that induce basophil/mast cell degranulation consist of at least five molecules on the outer surface of the cell: at least two IgE molecules usually of different antibody specificity; each bound to an α-chain of an FcER1 and an allergen with at least two epitopes, recognized by IgE molecules. While the crystal structure of complexes containing the interacting portions of the FcER1 and IgE molecules have been resolved, much less is known about the structural requirements of specific allergens to participate in the formation of activating complexes. Further, identifying these epitopes is a critical step in understanding the structural requirements for allergens to complete the pentameric complex that signals the basophil or mast cell to activate and release its mediators and other bioactive molecules.
Since avoidance of allergens is usually not a practical approach for managing hypersensitivity to outdoor plants, pharmacological therapy with anti-histamines, leukotriene antagonists and topical steroids are the mainstays of current therapy. However, these modalities have their limitations and adverse effects. Preventive or therapeutic immunization (immunotherapy) holds the greatest promise of preventing and treating acute hypersensitivity diseases. However, current allergy immunotherapy requires frequent injection of increasing amounts of crude extracts of the offending allergen and takes months to years to become effective. Immunization-induced changes in the inflammatory cascade are thought to be responsible for diminishing or abolishing the allergic reactions to natural exposure. The production of specific IgG antibodies may interfere with the delivery of the allergens to mast cells or the development of IgE-containing, activating complexes on the cell surface. Additionally, decreased numbers and activity of several inflammatory cell groups have been seen after allergen immunotherapy. Most of these changes are thought to be secondary to shifts in the T helper cells from Th2 to Th1 group (10μ, 12). However, there is also evidence for T cell unresponsiveness or anergy after immunotherapy (13). Furthermore, the long term protection of this form of immunization is similar to those achieved with anti-microbial vaccines in that the effect can last for a number of years after stopping or reducing the frequency of injections (14).
Despite the fact that immunotherapy for allergic disease has been practiced for almost 100 years, it has yet to achieve its full potential. This is largely because injecting increasing doses of crude extracts of sensitizing agents carries a risk for generalized and potentially fatal anaphylaxis. To avoid anaphlaxis, the allergen injections must be started at very low doses and increased gradually through a long series of injections. Attempts to reduce the anaphylaxis risk by chemically modifying the allergens with agents like formaldehyde, which reduce the binding of patient's IgE to the injected allergens have failed because they can also reduce the immunogenicity of the allergens. Another approach is to clone the major allergens and disrupt the structure of one or more of their IgE epitopes by site-directed mutagenesis. However, a drawback of this approach is the high cost of testing the safety of each of the mutagenized allergens in human subjects.
An alternate approach to obtain modified allergens would be to identify naturally occurring homologues of the sensitizing allergens within the same or similar plants. In fact, some allergens are shown as expressed as a family of closely related proteins or isoforms within the same plant and species of plants (15-16 Ferreira et al., 1996: Ferreira et al., 1997).
Previous studies identified two major allergens in the pollen of the mountain cedar tree. The first of these was named Jun a 1 (17 Midoro-Horiuti et al., 1999) because of its similarity to Cry j 1, an important allergen of Japanese cedar. Two cypress trees from southern Europe were later found to express highly allergenic homologues of Jun a1. Jun a1 dominates the allergic response to mountain cedar pollen and is therefore a therapeutic target in cedar pollinosis. Additionally, four linear IgE epitopes were mapped on the surface of Jun a1 (18 Czerwinski et al., 2005).
Despite these advances, the prior art is deficient in the identification of effective therapeutic agents that can prevent allergens from inducing allergic reactions. The present invention fulfills this long-standing need and desire in the art.